Evaluating UiO-66 Metal–Organic Framework Nanoparticles as Acid-Sensitive Carriers for Pulmonary Drug Delivery Applications

Abstract

Developing novel drug carriers for pulmonary delivery is necessary to achieve higher efficacy and consistency for treating pulmonary diseases while limiting off-target side effects that occur from alternative routes of administration. Metal–organic frameworks (MOFs) have recently emerged as a class of materials with characteristics well-suited for pulmonary drug delivery, with chemical tunability, high surface area, and pore size, which will allow for efficient loading of therapeutic cargo and deep lung penetration. UiO-66, a zirconium and terephthalic acid-based MOF, has displayed notable chemical and physical stability and potential biocompatibility; however, its feasibility for use as a pulmonary drug delivery vehicle has yet to be examined. Here, we evaluate the use of UiO-66 nanoparticles (NPs) as novel pulmonary drug delivery vehicles and assess the role of missing linker defects in their utility for this application. We determined that missing linker defects result in differences in NP aerodynamics but have minimal effects on the loading of model and therapeutic cargo, cargo release, biocompatibility, or biodistribution. This is a critical result, as it indicates the robust consistency of UiO-66, a critical feature for pulmonary drug delivery, which is plagued by inconsistent dosage because of variable properties. Not only that, but UiO-66 NPs also demonstrate pH-dependent stability, with resistance to degradation in extracellular conditions and breakdown in intracellular environments. Furthermore, the carriers exhibit high biocompatibility and low cytotoxicity in vitro and are well-tolerated in in vivo murine evaluations of orotracheally administered NPs. Following pulmonary delivery, UiO-66 NPs remain localized to the lungs before clearance over the course of seven days. Our results demonstrate the feasibility of using UiO-66 NPs as a novel platform for pulmonary drug delivery through their tunable NP properties, which allow for controlled aerodynamics and internalization-dependent cargo release while displaying remarkable pulmonary biocompatibility.

Nanoparticle Internalization Promotes the Survival of Primary Macrophages

“…Unsurprisingly, the role of material selection is critically important to tuning and directing these responses. Some materials used to fabricate nano-and microparticles have been shown to cause strong inflammatory or toxic effects on macrophages [7], while recent advances in biomaterials have elucidated classes of modular materials with strong biocompatibility [8][9][10][11]. Early generations of particulate therapeutics sought engineering solutions that avoided internalization by phagocytic immune cells to ensure successful cargo delivery [12,13]; however, an emerging alternative is to promote controlled interactions with innate immune cells to regulate immune response [14,15].…”

Biomaterials-Based Opportunities to Engineer the Pulmonary Host Immune Response in COVID-19

“… 273 Similarly, metal–organic framework (MOF) nanoparticles were loaded with dexamethasone and evaluated for pulmonary delivery. 274 Some other methods that have been developed to deliver corticosteroids include delivery of solid lipid nanoparticles loaded with budesonide for pulmonary drug delivery 275 and dexamethasone for potential lung targeting, 276 itraconazole nanoparticle-based dry powders for aerosol delivery of budesonide, 277 cross-linked copolymers of methyl methacrylate, N , N -dimethylaminoethyl methacrylate, and butyl methacrylate monomers designed to load hydrophobic corticosteroids. 278 Notably, dexamethasone-loaded PLGA microparticles were utilized to polarize macrophages toward an anti-inflammatory phenotype and resulted in a significant suppression of pro-inflammatory genes and TNF-α secretion.…”

Doxorubicin Loaded-UiO-66-NH2 Coated With Poly(N-Vinylcaprolactam) For Controlled Release of Doxorubicin Against A549 Lung Cancer

“…The nanosized-MOFs (NMOFs) prepared by the microwave heating method exhibited unique physic-chemical properties in comparison to the micrometer scale of MOFs [1,8]. The advantages of MOFs compared with other inorganic drug delivery systems (DDS) are the high encapsulation e ciency and their easier functionalization for targeted delivery [9][10][11][12][13][14]. UiO-66 MOFs ([Zr6O4(OH)4]) with high stability and high biocompatibility as well as good biodegradability and high speci c surface area had a high potential for delivery of anticancer drugs [15][16][17].…”